Association of peripheral inflammatory markers with chronic fatigue in a population-based sample

Alterations in the innate immune response may contribute to the pathogenesis of chronic fatigue syndrome (CFS). However, studies have been limited by small sample sizes, use of patients from tertiary care settings, inappropriate selection of controls, and failure to control for confounding demographic, medical and behavioral factors independently associated with immune activity. It is also not known whether specific symptoms account for observed associations between CFS and the innate immune response. To address these limitations, the current study examined plasma concentrations of high-sensitivity c-reactive protein (hs-CRP), white blood cell count (WBC) and a combined inflammation factor in a large population-based sample. Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with CFS (n = 102) and in subjects with unwellness symptoms that did not meet diagnostic criteria for CFS (defined as “insufficient fatigue” [ISF]) (n = 240) when compared to subjects who were well (n = 115). Log transformed WBC was increased in ISF and was increased at a trend level in CFS. The combined inflammation factor was increased in both CFS and ISF. Subjects with CFS and ISF did not differ on any of the inflammation measures. In the entire subject population, the physical component summary score (PCS), but not the mental component summary score (MCS), from the Medical Outcomes Study Short Form-36 (SF-36) was negatively associated with each of the inflammation measures. Depressive symptoms were also associated with increased log hs-CRP. After adjustment for age, sex, race, location of residence, BMI, depressive status and immune-modulating medications, subjects classified as ISF continued to demonstrate increased log hs-CRP, WBC and elevations on the inflammation factor when compared to well controls; however, associations between CFS and log hs-CRP and the inflammation factor were no longer statistically significant. After adjustment, PCS score also remained independently associated with each of the inflammation measures. These findings support a role for innate immune activation in unexplained fatigue and unwellness, but do not suggest that immune activation is specific to CFS.     

Coping strategies in twins with chronic fatigue and chronic fatigue syndrome

Objectives: Individuals with chronic fatigue and chronic fatigue syndrome (CFS) face debilitating symptoms as well as stressful life situations that may result from their condition. The goal of this study was to examine the coping strategies used by fatigue-discordant twin pairs. Methods: We utilized a co-twin design to assess how twin pairs discordant for chronic fatigue and CFS cope with stress. All twin pairs were administered the Revised Ways of Coping Checklist. Results: Overall, the pattern of coping strategies was similar for fatigued and non-fatigued twins. However, twins with chronic fatigue or CFS utilized more avoidance strategies than their non-fatigued counterparts; those with chronic fatigue also used more avoidance relative to problem-focused coping than their co-twins. Conclusions: These results suggest that while fatigue-discordant twins generally exhibit similar behavior patterns in order to cope with stress, there may be an association between fatigue and avoidance coping. Future research should focus on the role of avoidance and its relationship to fatiguing illnesses.     

Factor analysis of symptoms among subjects with unexplained chronic fatigue: what can we learn about chronic fatigue syndrome?

OBJECTIVE: Chronic fatigue syndrome (CFS) case definitions agree that fatigue must be unexplained, debilitating and present for at least 6 months, but they differ over accompanying symptoms. Our objective was to compare the 1994 CFS case-defining symptoms with those identified by factor analysis. METHODS: We surveyed the Wichita population and measured the occurrence of 21 symptoms in 1391 chronically fatigued subjects who did not report fatigue-associated medical or psychiatric conditions. We used factor analyses to identify symptom dimensions of fatigue and cluster analysis to assign subjects to subgroups. RESULTS: Forty-three subjects had CFS. We confirmed three factors: musculoskeletal, infection and cognition-mood-sleep, essentially defined by CFS symptoms. Although factor scores were higher among CFS subjects, CFS and non-CFS distributions overlapped substantially. Three clusters also showed overlap between CFS and non-CFS subjects. CONCLUSION: CFS symptomatology is a multidimensional phenomenon overlapping with other unexplained fatiguing syndromes and this must be considered in CFS research.     

Unraveling the role of perfectionism in chronic fatigue syndrome: is there a distinction between adaptive and maladaptive perfectionism?

In the current study, we investigated whether the distinction between adaptive (i.e. high personal standards) and maladaptive (i.e. concern over mistakes and doubt about actions) perfectionism that has been found in the literature, is also valid in patients with chronic fatigue syndrome (CFS). We hypothesized that maladaptive, but not adaptive, perfectionism would be significantly and positively related to severity of fatigue and depression in CFS. We examined this hypothesis in a sample of 192 CFS patients using structural equation modelling (SEM). Although the two perfectionism dimensions were related to each other, results supported a model in which only maladaptive perfectionism was positively related to severity of fatigue and depression. Further, we found that depression fully mediated the effect of maladaptive perfectionism on fatigue. The results suggest that adaptive and maladaptive perfectionism are two distinct, albeit related, dimensions in CFS. Findings of this study have important implications for theory and treatment of CFS, particularly for cognitive-behavioral treatment.     

Defensive coping styles in chronic fatigue syndrome

OBJECTIVE: The cognitive-behavioral model of chronic fatigue syndrome (CFS) proposes that rigidly held beliefs act to defend individuals against low self-esteem. This study is the first to investigate the prevalence of a potential mechanism, the Defensive High Anxious coping style, among individuals with CFS. METHODS: The study comprised 68 participants (24 CFS; 24 healthy volunteers; 20 chronic illness volunteers). Participants completed the Bendig short form of the Taylor Manifest Anxiety Scale (B-MAS) and the Marlowe-Crowne Social Desirability Scale (MC) in order to ascertain the distribution of participants in each group within the four coping styles defined by Weinberger et al. [J. Abnorm. Psychol. 88 (1979) 369]. RESULTS: A greater number of participants in the CFS group (46%) were classified as Defensive High Anxious compared to the two comparison groups [chi(2)(2)=8.84, P=.012]. CONCLUSION: This study provides support for the existence of defensive coping mechanisms as described by the cognitive-behavioral model of CFS. Furthermore, it has been suggested that this particular coping style may impinge directly on physical well being through similar mechanisms as identified in CFS, and further research linking these areas of research is warranted.     

Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome

OBJECTIVE: It has been suggested that a hypofunctional hypothalamic-pituitary-adrenal (HPA) axis in chronic fatigue syndrome could result in an exaggerated release of pro-inflammatory cytokines during stress. As pro-inflammatory cytokines are involved in the induction of sickness behavior and thus constitute a potential physiological correlate of stress-induced symptom exacerbation in chronic fatigue syndrome, we set out to evaluate the LPS-induced production of pro-inflammatory cytokines during psychosocial stress in CFS and healthy controls. METHOD: Twenty-one CFS patients and 20 healthy controls matched for age and gender underwent a standardized psychosocial stress test (Trier social stress test, TSST). Adrenocorticotropine hormone (ACTH), salivary cortisol and plasma cortisol levels were measured before and repeatedly following exposure to the stressor. Lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-alpha were assessed at baseline as well as 10 and 60 min after the stress test. RESULTS: CFS patients showed an inverse stress-induced response pattern of LPS-stimulated cytokines responses in comparison to healthy controls, i.e. stimulated cytokine production decreased shortly after stress in CFS patients, while it increased in controls. Fatigue scores and basal LPS-induced cytokine levels were significantly associated for TNF-alpha in controls and for both cytokines in CFS patients. Stress-induced changes in stimulated cytokine production were not associated with general fatigue scores in the control group, whereas in the CFS group, fatigue scores were significantly correlated with integrated levels of LPS-induced cytokines. However, partial correlations revealed that these results were due to the high correlations with basal LPS-induced cytokine levels. CONCLUSION: CFS patients do not show an exaggerated secretion of LPS-induced cytokines. Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. Possible intracellular mechanisms, such as for example an enhanced sensitivity to inhibitory effects of glucocorticoids, a diminished responsivity to catecholaminergic stimulation, and a disruption of intracellular activation are discussed. Basal levels of stimulated pro-inflammatory Il-6 levels are generally related to fatigue scores. However, in CFS patients this association is of greater magnitude and can also be observed for TNF-alpha.     

Medically evaluated psychological and physical health of Australian Gulf War veterans with chronic fatigue

OBJECTIVE: The aim of this study was to evaluate fatigue in Australian Gulf War veterans and a military comparison group according to the 1994 chronic fatigue syndrome (CFS) definition and investigate the relation with exposures. METHODS: Comprehensive medical, psychological and reported exposure assessments of 1,456 veterans and 1,588 comparison group in a cross-sectional study. RESULTS: More Gulf War veterans had fatigue at all levels than did the military comparison group. The findings may be at least partly explained as an "active-deployment effect." The odds ratios increased with increasing clinical evaluation of the nature of the fatigue, even after adjustment for current psychiatric disorders in addition to other possible confounding factors. CONCLUSION: Medically unexplained chronic fatigue was more common, but not more disabling, in veterans than in the comparison group, but veterans with unexplained chronic fatigue had poorer health than veterans without. Within both populations, CFS is uncommon and at a similar level to the general community.     

Obesity and coping in childhood

The aim of this study was to investigate everyday coping styles in obese children in comparison to healthy controls in dependence of gender. Furthermore, the correlations of eating behavior with coping styles were examined. In addition, groups with highest and lowest extremal scores in eating behavior were compared. Patients (N = 58) aged from 11 to 13 years, who took part in an in-patient education program, were asked to complete the German Coping Questionnaire for Children and Adolescents (Hampel et al. 2001) and the Dutch Eating Behavior Questionnaire for Children (Franzen u. Florin 1997). Healthy controls were matched by age and gender and were asked to fill out the SVF-KJ. No differences between coping styles of obese children and adolescents and healthy controls were found. In obese children and adolescents, emotional and external eating behavior were positively correlated with maladaptive coping strategies. In comparison to previous findings in chronically ill children, differences in obese children and adolescents and healthy controls on coping styles could not be confirmed in the present study. However, results support that the eating behavior of obese children and adolescents is influenced by coping styles.     

Examination of Cloninger's basic dimensions of personality in fatiguing illness: chronic fatigue syndrome and multiple sclerosis

Relatively few studies have examined the personality characteristics of patients with chronic fatigue syndrome (CFS). The personality profiles of 38 CFS subjects were compared with 40 healthy controls and 40 subjects with multiple sclerosis (MS), a chronic illness that shares many symptoms with CFS (e.g., fatigue), but has a known neurological substrate. Subjects were examined within Cloninger's biosocial theory of personality, which delineates basic dimensions of temperament. Both illness groups displayed similarly elevated levels of Harm Avoidance, and lower levels of Reward Dependence as compared with healthy controls. The MS group showed a lower level of Persistence than controls and CFS subjects. Implications for the relationship between chronic illness and personality are discussed.     

Neurobehavioral deficits associated with chronic fatigue syndrome in veterans with Gulf War unexplained illnesses.

Gulf War unexplained illnesses (GWUI) are a heterogeneous collection of symptoms of unknown origin known to be more common among veterans of the Gulf War than among nonveterans. In the present study we focused on one of these unexplained illnesses. We tested the hypothesis that in a sample of Persian Gulf War veterans chronic fatigue syndrome (CFS) was associated with cognitive deficits on computerized cognitive testing after controlling for the effects of premorbid cognitive differences. We obtained Armed Forces Qualification Test (AFQT) data acquired around the date of induction into the military on 94 veterans of the Gulf War, 32 with CFS and 62 healthy controls. Controls performed better than participants diagnosed with CFS on the AFQT. Cognitive deficits were associated with CFS on 3 of 8 variables after the effect of premorbid AFQT scores was removed with ANCOVA.     

Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome

OBJECTIVE: Enhancement of negative feedback control of the HPA axis in patients with chronic fatigue syndrome (CFS) has been reported using the low dose dexamethasone suppression test. We have developed the use of prednisolone (5mg) as a more physiologically appropriate alternative to dexamethasone in the investigation of mild degrees of glucocorticoid resistance or supersensitivity. The objective of the study was to use this test to look for alterations in negative feedback control of the HPA axis in CFS patients. METHODS: Fifteen patients with CFS were recruited after fulfilling strict criteria including the absence of comorbid psychiatric diagnosis. They collected urine between 0900 and 1800h and saliva at 0900h pre-prednisolone. At midnight, they took prednisolone (5mg) orally and then collected urine and saliva at the same intervals the following day. RESULTS: Salivary cortisol was lower in CFS subjects pre-prednisolone than controls. Urinary cortisol metabolites were lower in CFS subjects pre-prednisolone, but did not reach significance. Both measures were significantly lower in CFS subjects post-dose. Mean percentage suppression of both salivary cortisol and urinary cortisol metabolites was significantly higher in CFS compared to controls. CONCLUSION: There is enhanced sensitivity of the HPA axis to negative feedback in CFS as demonstrated using the prednisolone suppression test. This provides further evidence of alterations in the control of the HPA axis in patients with established CFS.     

Fatigue syndromes: a comparison of chronic "postviral" fatigue with neuromuscular and affective disorders.

Patients (n = 47) presenting to a neurological centre with unexplained chronic "postviral" fatigue (CFS) were studied prospectively. Controls were patients with peripheral fatiguing neuromuscular diseases and inpatients with major depression in a psychiatric hospital. Seventy-two percent of the CFS patients were cases of psychiatric disorder, using criteria that excluded fatigue as a symptom, compared with 36% of the neuromuscular group. There was no difference in subjective complaints of physical fatigue between all groups. Mental fatigue and fatigability was equally common in CFS and affective patients, but only occurred in those neuromuscular patients who were also cases of psychiatric disorder. Overall, the CFS patients more closely resembled the affective than the neuromuscular patients. Attribution of symptoms to physical rather than psychological causes was the principal difference between matched CFS and psychiatric controls. The symptoms of "postviral" fatigue had little ability to discriminate between CFS and affective disorder. The fatigue in CFS appeared central in origin, suggesting it is not primarily a neuromuscular illness. The implications for research and treatment of chronic fatigue are discussed.     

The relationship between posttraumatic stress disorder, illness cognitions, defence styles, fatigue severity and psychological well-being in chronic fatigue syndrome

This study investigated, firstly, the rate of posttraumatic stress disorder (PTSD) and the level of psychological well-being amongst people with chronic fatigue syndrome (CFS); and secondly, the extent to which illness cognitions, defence styles and PTSD symptom severity related to fatigue severity and psychological well-being. Seventy-eight participants with a diagnosis of CFS completed the Chalder Fatigue Scale, the General Health Questionnaire-28, the Posttraumatic Stress Diagnostic Scale, the Illness Cognition Questionnaire and the Defence Style Questionnaire. Fifty-nine participants were recruited from the general public to form the non-fatigued control group. CFS participants had significantly higher levels of PTSD symptoms, lower levels of psychological well-being and more traumatic life events compared to the non-fatigued controls. Trauma exposure and PTSD severity both predicted CFS status. However, regression analyses demonstrated no significant relationship between PTSD symptoms and fatigue severity or the degree of psychological well-being. ‘Helplessness’ predicted both physical and mental fatigue and psychological well-being, whilst the ‘mature’ defence styles predicted fatigue severity only. The results offer support to previous research showing that the rate of traumatic life events and PTSD are significantly higher amongst the CFS population. The lack of relationship between PTSD symptoms and fatigue severity or psychological well-being indicates that these processes may operate independently of one another, via different appraisal processes. This study focused on fatigue severity, but it may be that the role of pain in CFS is a key element in the previously reported association between PTSD and CFS.     

Attentional bias towards health-threat information in chronic fatigue syndrome

OBJECTIVE: To investigate whether individuals with chronic fatigue syndrome (CFS) show an attentional bias towards health-threat information. METHODS: Attentional bias (AB) was assessed in individuals with CFS and healthy controls using a visual probe task which presented health-threat and neutral words and pictures for 500 ms. Self-report questionnaires were used to assess CFS symptoms, depression, anxiety, and social desirability. RESULTS: Compared to a healthy control group, the CFS group showed an enhanced AB towards heath-threat stimuli relative to neutral stimuli. The AB was not influenced by the type of stimulus (pictures vs. words). CONCLUSION: The finding of an AB towards health-threat information in individuals with CFS is supportive of models of CFS which underlie cognitive behavior therapy.     

Symptom patterns in long-duration chronic fatigue syndrome

OBJECTIVE: Our objective was to evaluate symptom patterns in patients with chronic fatigue syndrome (CFS) who were ill for 10 or more years. METHODS: This cross-sectional self-report study compared patient groups with long-duration (median = 18 years; n = 258) and short-duration (median = 3 years; n = 28) CFS to a group of healthy significant others (n = 79) on symptomatic, neurocognitive, and psychological variables. Data were gathered from a 574-item postal questionnaire. RESULTS: A principal-components analysis of CFS symptom data yielded a three-factor solution: cognitive problems; flu-like symptoms; and neurologic symptoms. Compared with the short-duration CFS group, the long-duration group had significantly higher CFS symptom severity scores (p < 0.04), largely attributable to increased cognitive difficulties. A subgroup comparison of subjects ill for < 3 years versus those ill 4-7 years suggested that denial coping strategies were more likely in those participants with the shorter illness duration. Significant differences between both CFS groups and healthy controls were found in a number of comorbid disorders. Participants with CFS most often endorsed immune/viral abnormalities and persistent stress as important perceived causes of their illness. CONCLUSION: Participants with long-duration CFS reported a large number of specific cognitive difficulties that were greater in severity than those reported by participants with short-duration CFS. The pattern of comorbid disorders in the CFS groups was consistent with hypersensitivity and viral reactivation hypotheses.     

Impact of a maximal exercise test on symptoms and activity in chronic fatigue syndrome

OBJECTIVE: This study examined the effects of exercise on symptoms and activity in chronic fatigue syndrome (CFS). METHODS: Twenty CFS patients and 20 neighborhood controls performed an incremental exercise test until exhaustion. Fatigue, muscle pain, minutes spent resting, and the level of physical activity were assessed with a self-observation list. Physical activity was assessed with an actometer as well. Data were obtained 3 days before the maximal exercise test (MET) up to 5 days thereafter. RESULTS: For CFS patients, daily observed fatigue was increased up to 2 days after the exercise test. For controls, self-observed fatigue returned to baseline after 2 h. Both CFS patients and controls spent more minutes resting on the day before and on the day after the MET. For CFS patients, self-observed minutes resting increased on the day of the exercise test. For neither group, a decrease of actometer recorded or self-observed physical activity after exercise was found. CONCLUSION: Fatigue in CFS patients increased after exercise, but the level of actual physical activity remained unchanged.     

Chronic fatigue syndrome and sexual dysfunction

OBJECTIVE: The study was undertaken to determine if ambulant female patients with the chronic fatigue syndrome (CFS) report problems with their sexual functioning. METHODS: We studied 35 female CFS patients and 36 healthy female controls. The severity of CFS was measured with a fatigue questionnaire and the presence and severity of sexual dysfunction with a questionnaire about sexual functioning. RESULTS: The mean fatigue score was 24.8 in the CFS patients and 11.9 in the controls (P=.000). No increase in sexual dysfunction was found in the CFS group. The control group showed negative correlations between the score of the fatigue questionnaire and the frequency of "sexual fantasies," "(desire for) sexual contact" and "satisfaction with sex life." Such correlations were absent in the CFS group. CONCLUSION: The satisfaction with sex life was similar in patients and controls. The results suggest that patients and controls have a different perception of fatigue.     

Corticomotor excitability and perception of effort during sustained exercise in the chronic fatigue syndrome.

OBJECTIVE: We have investigated the possibility of a central basis for the complaints of fatigue and poor exercise tolerance in subjects with chronic fatigue syndrome (CFS). METHODS: Transcranial magnetic stimulation of the motor cortex was used to measure sequential changes in motor evoked potential (MEP) amplitude, post-excitatory silent period (SP) duration and twitch force of the biceps brachii muscle during a 20% maximum isometric elbow flexor contraction maintained to the point of exhaustion. Ten patients with post-infectious CFS and 10 age- and sex-matched control subjects were studied. Results were analysed using non-parametric repeated measures analysis of variance (Friedman's test) and Mann-Whitney U-tests for intra- and inter-group comparisons respectively. RESULTS: Mean endurance time for the CFS group was lower (13.1+/-3.2 min, mean +/- SEM) than controls (18.6+/-2.6 min, P < 0.05) and CFS subjects reported higher ratings of perceived exertion. During the exercise period MEP amplitude and SP duration increased in both groups but to a lesser extent in CFS subjects. Interpolated twitch force amplitude also increased during exercise, being more pronounced in CFS subjects. CONCLUSION: The findings are in keeping with an exercise-related diminution in central motor drive in association with an increased perception of effort in CFS.     

Hormonal responses to exercise in chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a debilitating disease characterized by severe, unexplained fatigue and postexertional exacerbation of symptoms. We examined basal endocrine function in a group of CFS patients and a carefully matched group of sedentary controls. The subjects then completed a graded, maximal exercise test on a treadmill, and additional blood samples were drawn 4 min and a day after the end of exercise. There were no differences in basal hormone levels before exercise. Plasma adrenocorticotropin, epinephrine, prolactin and thyrotropin responses 4 min after exercise were lower in the CFS group, but the growth hormone response may have been exaggerated, and the plasma norepinephrine response was similar to that in controls. The next day, there were no differences in hormone levels between the groups, which suggests that long-term changes in endocrine function are unlikely to be a cause of the prolonged fatigue that occurs in CFS patients after a bout of exertion.     

Motor cortex excitability in chronic fatigue syndrome.

OBJECTIVE: To use transcranial magnetic stimulation (TMS) to define motor cortical excitability in chronic fatigue syndrome (CFS) subjects during a repetitive, bilateral finger movement task. METHODS: A total of 14 CFS patients were tested and compared with 14 age-matched healthy control subjects. TMS of the motor cortex (5% above threshold) was used to elicit motor evoked potentials (MEPs). Subjects performed regular (3-4/s) repetitive bilateral opening-closing movements of the index finger onto the thumb. MEPs of the first dorsal interosseus (FDI) were measured before, immediately following exercise periods of 30, 60 and 90 s, and after 15 min of rest. RESULTS: Performance, defined by rate of movement, was significantly slower in CFS subjects (3.5/s) than in controls (4. 0/s) independent of the hand measured. The rate, however, was not significantly affected by the exercise duration for either group. The threshold of TMS to evoke MEPs from the FDI muscle was significantly higher in CFS than in control subjects, independent of the hemisphere tested. A transient post-exercise facilitation of MEP amplitudes immediately after the exercise periods was present in controls independent of the hemisphere tested, but was absent in CFS subjects. A delayed facilitation of MEPs after 15-30 min of rest was restricted to the non-dominant hemisphere in controls; delayed facilitation was absent in CFS subjects. CONCLUSIONS: Individuals with CFS do not show the normal fluctuations of motor cortical excitability that accompany and follow non-fatiguing repetitive bimanual finger movements.